Aged Transgenic Mice With Increased Glucocorticoid Sensitivity in Pancreatic β-Cells Develop Diabetes

Abstract

Glucocorticoids are diabetogenic hormones because they decrease glucose uptake, increase hepatic glucose production, and inhibit insulin release. To study the long-term effects of increased glucocorticoid sensitivity in ␤-cells, we studied transgenic mice overexpressing the rat glucocorticoid receptor targeted to the ␤-cells using the rat insulin I promoter. Here we report that these mice developed hyperglycemia both in the fed and the overnight-fasted states at 12-15 months of age. Progression from impaired glucose tolerance, previously observed in the same colony at the age of 3 months, to manifest diabetes was not associated with morphological changes or increased apoptosis in the ␤-cells. Instead, our current results suggest that the development of diabetes is due to augmented inhibition of insulin secretion through ␣ 2 -adrenergic receptors (␣ 2 -ARs). Thus, we found a significantly higher density of ␣ 2 -ARs in the islets of transgenic mice compared with controls, based on binding studies with the ␣ 2 -AR agonist UK 14304. Furthermore, incubation of islets with benextramine, a selective antagonist of the ␣ 2 -AR, restored insulin secretion in response to glucose in isolated islets from transgenic mice, whereas it had no effect on control islets. These results indicate that the chronic enhancement of glucocorticoid signaling in pancreatic ␤-cells results in hyperglycemia and impaired glucose tolerance. This effect may involve signaling pathways that participate in the regulation of insulin secretion via the ␣ 2 -AR. Diabetes 53 (Suppl. 1): S51-S59, 2004

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene–environment interactions

“…66 Finally, aged transgenic mice that display increased sensitivity to glucocorticoids in pancreatic beta-cells develop diabetes. 67 These results can be relevant for humans -a recent study has shown that a polymorphism in the glucocorticoid receptor gene is associated with decreased sensitivity to glucocorticoids and decreased insulin and cholesterol levels in vivo. 68 A single nucleotide polymorphism on exon 2 of the glucocorticoid receptor gene is associated with increased sensitivity to glucocorticoids and obesity in nondiabetic subjects.…”

Glucocorticoids, metabolism and metabolic diseases

“…Further evidence for the ability of GCs to suppress insulin output was obtained in vivo in experiments with mice overexpressing the GR in pancreatic β-cells. This genetic modification leads to decreased insulin secretion accompanied by reduced glucose tolerance in adult mice and hyperglycemia in aged mice [250,251]. In the latter case, enhanced α-adrenergic receptor signaling was reported in GRoverexpressing cells, a finding that has been linked to suppression of insulin release [251].…”

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

“…When these transgenic mice aged, hyperglycaemia developed together with marked glucose intolerance and reduced in vivo and ex vivo GSIS. Remarkably, no change in b-cell apoptosis was observed in these mice (Davani et al 2004). This deterioration in GSIS was prevented by incubating islets with benextramine (a selective a2-adrenergic receptor antagonist), suggesting the involvement of adrenergic signals.…”

“…In an attempt to analyse whether GCs have any direct effects on b-cells in vivo independent of peripheral GC actions, a transgenic mice model that specifically overexpresses GR in these cells was generated (Delaunay et al 1997, Davani et al 2004. These mice were normoglycaemic, but displayed glucose intolerance associated with reduced insulin secretion during a glucose load (Delaunay et al 1997).…”